Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum

Journal article

Excess cellular heme is toxic, and malaria parasites regulate its levels during hemoglobin digestion. Aminoacyl-tRNA synthetases are ubiquitous enzymes, and of these, arginyl-tRNA synthetase (RRS) is unique as its enzymatic product of charged tRNA is required for protein synthesis and degradation. We show that Plasmodium falciparum arginyl-tRNA synthetase (PfRRS) is an active, cytosolic, and monomeric enzyme. Its high-resolution crystal structure highlights critical structural differences with the human enzyme. We further show that hemin binds to and inhibits the aminoacylation activity of PfRRS. Hemin induces a dimeric form of PfRRS that is thus rendered enzymatically dead as it is unable to recognize its cognate tRNAarg. Excessive hemin in chloroquine-treated malaria parasites results in significantly reduced charged tRNAarg levels, thus suggesting deceleration of protein synthesis. These data together suggest that the inhibition of Plasmodium falciparum arginyl-tRNA synthetase can now be synergized with existing antimalarials for more potent drug cocktails against malaria parasites.

Authors: Jain, V; Yogavel, M; Sharma, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Structure More from this journal
• Volume: 24
• Issue: 9
• Pages: 1476-1487
• Publication date: 2016-08-05
• Acceptance date: 2016-06-20
• DOI: 10.1016/j.str.2016.06.018
• EISSN: 1878-4186
• ISSN: 0969-2126